The objective of this proposal is to clarify the mechanism of tumor promotion with special reference to the role of cyclic nucleotides as well as other agents in the promotion process. The biological antagonism between the promoter, phorbol myristate acetate (PMA), and promotion inhibitors such as butyric acid in promotion and differentiation may depend on their biochemical antagonism in coupling beta-adrenergic receptors to adenyl cyclase. We have shown that PMA stimulates a prolonged cyclic GMP synthesis and blocks the butyric acid coupling effect in mouse epidermis. Further studies in epidermis and cells in culture will involve correlations of this biochemical antagonism with promotion and differentiation. These probably involve membrane receptors for PMA which will be characterized. The effects of PMA on protein phosphorylation and calcium metabolism which often involve cyclic nucleotides will also be determined. These studies should clarify carcinogenic and anti-carcinogenic mechanisms and thus help in the control of cancer.